Volume 122, Issue 7, Pages 1913-1923 (June 2002) COX-1 and 2, intestinal integrity, and pathogenesis of nonsteroidal anti-inflammatory drug enteropathy in mice  Gudmundur Sigthorsson, Robert J. Simpson, Matthew Walley, Andrew Anthony, Russell Foster, Christoph Hotz–Behoftsitz, Abbas Palizban, Joaquim Pombo, Jo Watts, Scott G. Morham, Ingvar Bjarnason  Gastroenterology  Volume 122, Issue 7, Pages 1913-1923 (June 2002) DOI: 10.1053/gast.2002.33647 Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 1 Small intestine PGE2 levels and ulcer counts. Open bars in the upper part of the Figure represent mean PGE2 levels (as percentage of untreated COX-1+/+) in wild-type animals; shaded bars, the levels in COX-deficient mice (± standard error [SE]). Small intestine ulcer counts (mean ± SE) carried out in separate groups of animals are shown in the lower part of the Figure. The number of animals in each group varied from 5 to 16. *Significantly less than untreated COX-1+/+ animals (P < 0.001). +Significantly less than untreated COX-1+/+ animals (P < 0.001) and significantly (P < 0.05) less than that of untreated or DMSO-treated COX-1−/− animals. All of the ulcer counts above 0 are significantly different from control or DMSO-treated animals. °Significantly (P < 0.05) fewer ulcers than in COX-1+/+ animals receiving 3.75 mg/kg indomethacin. αSignificantly (P < 0.05) more ulcers than in COX-1−/− animals receiving 3.75 mg/kg indomethacin. Gastroenterology 2002 122, 1913-1923DOI: (10.1053/gast.2002.33647) Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 2 Effect of COX-1 deletion on intestinal permeability after indomethacin administration. Baseline intestinal permeability did not differ significantly between the COX-1+/+ (n = 16/group) and COX-1−/− animals (n = 8/group). Indomethacin at both doses (n = 8/group) increased intestinal permeability significantly in the 1- to 25-hour period, with restoration of normal intestinal permeability at 72–96 hours. The 15-mg/kg dose increased intestinal permeability to a significantly greater extent than the 3.75-mg/kg dose. The boxes represent mean, and the bars represent ±SE; the open boxes are COX-1+/+ animals, and the shaded boxes are COX-1−/− animals. *Differs significantly (P < 0.01) from baseline. +Differs significantly (P < 0.01) from baseline and the 3.75 mg/kg indomethacin dose. Gastroenterology 2002 122, 1913-1923DOI: (10.1053/gast.2002.33647) Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 3 Effect of COX-1 deletion on intestinal inflammation after indomethacin administration. Baseline fecal excretion of GMP did not differ significantly (P > 0.8) between any of the groups. Solvent had no significant effect on fecal GMP concentrations, whereas both doses of indomethacin increased GMP concentrations significantly in both genotypes. The effect of a 15-mg/kg dose of indomethacin was significantly greater than that of the 3.75-mg/kg dose, but there was no significant difference between the COX-1+/+ and COX-1−/− animals at any time point. Bars represent the mean (±SE) daily fecal concentration of GMP. The open boxes are COX-1+/+ animals, and the shaded boxes are COX-1−/− animals. +Differs significantly (P < 0.01) from baseline. *Differs significantly (P < 0.001) from baseline. Gastroenterology 2002 122, 1913-1923DOI: (10.1053/gast.2002.33647) Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 4 Microscopic features of damage associated with indomethacin and COX-2 inhibition or absence. (A) Normal small bowel (magnification 20×). (B) Acute damage 24 hours after indomethacin (3.75 mg/kg) administration demonstrating a punched-out ulcer (magnification 30×). (C) Representative damage in a COX-2−/− animal demonstrating a chronic-looking ileal ulcer (magnification 30×), distinctively different from the acute indomethacin-induced ulcer. Long-term COX-2 inhibition with celecoxib was associated with the same pathology as in the COX-2−/− animals. Gastroenterology 2002 122, 1913-1923DOI: (10.1053/gast.2002.33647) Copyright © 2002 American Gastroenterological Association Terms and Conditions